Joyce O’Shaughnessy, MD: How is the availability of olaparib now changing your practice for the triple-negative and the ER-positive patients?

Nadine Tung, MD: I completely agree with Tiffany—for triple-negative disease, if I were going to reach for a single agent, I would reach for olaparib. If I needed a doublet and somebody was very sick, that’s a different story, in the triple-negative setting. We don’t have a direct comparison to platinum. If you do what you’re not supposed to and look at a cross-study comparison of the TNT trial and the OlympiAD trial, the progression-free survival looks pretty much the same. The response rate in the first-line setting looks pretty much the same. But I think the toxicity would be so much less. So, to me, at this point, a single-agent option for triple-negative—I would reach for olaparib, as Tiffany said.

The ER-positive setting is interesting. In the OlympiAD trial, those were endocrine-resistant patients. They had all, pretty much, seen endocrine therapy in the metastatic setting. They’re more like the patients in the PALOMA-3 and MONARCH 2 trials. Almost none of them had seen a CDK [cyclin-dependent kinase] 4/6 inhibitor. So I agree. I guess if you’re a purist, you would stay with endocrine therapy, as long as you felt that the patient was appropriate for it and you were getting a response. And then, when you’re going to move, use olaparib.

I think of the toxicity with these 2 oral agents. One could make an argument—if I had an ER-positive patient with a germline BRCA mutation who’d progressed on an AI [aromatase inhibitor], would I use a PARP inhibitor? Would I use a CDK4/6 inhibitor? There’s no direct comparison or data to really draw upon for that.

Joyce O’Shaughnessy, MD: That’s interesting. So you both would really favor going right to olaparib for the first-line treatment of a patient who is triple-negative, if he or she wasn’t very, very ill?

Nadine Tung, MD: I would.

Joyce O’Shaughnessy, MD: I would too. I haven’t had the opportunity to do it yet. It hasn’t come up yet, but I would do the same thing.

Nadine Tung, MD: Can I add 1 more comment? In the OlympiAD trial (again, it wasn’t platinum), compared with eribulin, compared with capecitabine, the time to respond was the same. It was about 45, 47 days. That’s important because we think, “Oh, a pill,” or, “Endocrine therapy,” and we say, “It’s going to take a long time to respond.” It was the same. So we need to get over that psychological barrier.

Joyce O’Shaughnessy, MD: It’s a little analogous to the CDK4/6 inhibitor issue in the first-line metastatic wild-type setting—not germline BRCA. It’s very effective therapy. If you have somebody in whom you would have given chemotherapy, are you comfortable using the pill instead? Again, the time to response is very, very quick. But it takes a little time to evolve those patterns, doesn’t it? I think we’re going to probably get there, more and more. So that’s really very interesting. The hope is that the median progression-free survival, when we move it up, will be much longer. And then, in the ER-positive patient, where there are so many other options, that first-line CDK4/6 inhibitor demonstrated a 24-month median progression-free survival. That’s pretty much a sign to stand up and salute.

Nadine Tung, MD: Again, those are endocrine-sensitive….

Joyce O’Shaughnessy, MD: Those are endocrine-sensitive patients. It’s really a mixture, where the luminal As outnumber the luminal Bs. The number is probably disproportionate. The BRCA2s would, perhaps, be considered a little bit more aggressive. It’s probably fair to say that the BRCA2s with ER-positive disease demonstrate more of a luminal B biology.

Nadine Tung, MD: Interesting. I think that ER-positive cases, in all the BRCA2 carriers, tend to be the luminal Bs, more so. They have higher Oncotype recurrence scores and higher proliferative rates. So they tend to be luminal B.

Joyce O’Shaughnessy, MD: Yes. All we’ve seen in the CDK4/6 studies has been the forest plots, where everybody benefits a great deal more. I don’t know that I could quote, yet, looking at PAM50, what the progression-free survival differences will be for the luminal As versus the luminal Bs. A lot of that is still ongoing.

Tiffany Traina, MD: Just thinking about where to sequence this, say we leave first-line off to the side? That’s where CDK4/6 inhibitors are? We’ve all had women with ER-positive disease who struggle with the bone-related adverse events from aromatase inhibitors or some of the mucositis from the mTOR [mammalian target of rapamycin] inhibitors. When you look at the toxicity profiles, olaparib, in that setting, would be pretty well tolerated and very reasonable to use for someone with ER-positive disease in the second-line setting, if they are having a hard time with endocrine therapy.

Joyce O’Shaughnessy, MD: We all gauge it—how many lines of endocrine therapy we give depends on what’s going on with the patient. How well did they do with the previous endocrine therapy? Everybody is going to be different, in terms of how many lines of endocrine therapy they receive. But it sounds like we’re all on the same page. Before we would go on to our next option, like oral capecitabine, for example (which we might have done next), we’d go on to olaparib. So that’s really interesting. We’re moving it up, and it’s really going to be interesting to see how that goes for the patient. We really hope we get those wonderful, durable responses.

Transcript Edited for Clarity

SELECTEDLANGUAGE

Transcript:

Joyce O’Shaughnessy, MD: How is the availability of olaparib now changing your practice for the triple-negative and the ER-positive patients?

Nadine Tung, MD: I completely agree with Tiffany—for triple-negative disease, if I were going to reach for a single agent, I would reach for olaparib. If I needed a doublet and somebody was very sick, that’s a different story, in the triple-negative setting. We don’t have a direct comparison to platinum. If you do what you’re not supposed to and look at a cross-study comparison of the TNT trial and the OlympiAD trial, the progression-free survival looks pretty much the same. The response rate in the first-line setting looks pretty much the same. But I think the toxicity would be so much less. So, to me, at this point, a single-agent option for triple-negative—I would reach for olaparib, as Tiffany said.

The ER-positive setting is interesting. In the OlympiAD trial, those were endocrine-resistant patients. They had all, pretty much, seen endocrine therapy in the metastatic setting. They’re more like the patients in the PALOMA-3 and MONARCH 2 trials. Almost none of them had seen a CDK [cyclin-dependent kinase] 4/6 inhibitor. So I agree. I guess if you’re a purist, you would stay with endocrine therapy, as long as you felt that the patient was appropriate for it and you were getting a response. And then, when you’re going to move, use olaparib.

I think of the toxicity with these 2 oral agents. One could make an argument—if I had an ER-positive patient with a germline BRCA mutation who’d progressed on an AI [aromatase inhibitor], would I use a PARP inhibitor? Would I use a CDK4/6 inhibitor? There’s no direct comparison or data to really draw upon for that.

Joyce O’Shaughnessy, MD: That’s interesting. So you both would really favor going right to olaparib for the first-line treatment of a patient who is triple-negative, if he or she wasn’t very, very ill?

Nadine Tung, MD: I would.

Joyce O’Shaughnessy, MD: I would too. I haven’t had the opportunity to do it yet. It hasn’t come up yet, but I would do the same thing.

Nadine Tung, MD: Can I add 1 more comment? In the OlympiAD trial (again, it wasn’t platinum), compared with eribulin, compared with capecitabine, the time to respond was the same. It was about 45, 47 days. That’s important because we think, “Oh, a pill,” or, “Endocrine therapy,” and we say, “It’s going to take a long time to respond.” It was the same. So we need to get over that psychological barrier.

Joyce O’Shaughnessy, MD: It’s a little analogous to the CDK4/6 inhibitor issue in the first-line metastatic wild-type setting—not germline BRCA. It’s very effective therapy. If you have somebody in whom you would have given chemotherapy, are you comfortable using the pill instead? Again, the time to response is very, very quick. But it takes a little time to evolve those patterns, doesn’t it? I think we’re going to probably get there, more and more. So that’s really very interesting. The hope is that the median progression-free survival, when we move it up, will be much longer. And then, in the ER-positive patient, where there are so many other options, that first-line CDK4/6 inhibitor demonstrated a 24-month median progression-free survival. That’s pretty much a sign to stand up and salute.

Nadine Tung, MD: Again, those are endocrine-sensitive….

Joyce O’Shaughnessy, MD: Those are endocrine-sensitive patients. It’s really a mixture, where the luminal As outnumber the luminal Bs. The number is probably disproportionate. The BRCA2s would, perhaps, be considered a little bit more aggressive. It’s probably fair to say that the BRCA2s with ER-positive disease demonstrate more of a luminal B biology.

Nadine Tung, MD: Interesting. I think that ER-positive cases, in all the BRCA2 carriers, tend to be the luminal Bs, more so. They have higher Oncotype recurrence scores and higher proliferative rates. So they tend to be luminal B.

Joyce O’Shaughnessy, MD: Yes. All we’ve seen in the CDK4/6 studies has been the forest plots, where everybody benefits a great deal more. I don’t know that I could quote, yet, looking at PAM50, what the progression-free survival differences will be for the luminal As versus the luminal Bs. A lot of that is still ongoing.

Tiffany Traina, MD: Just thinking about where to sequence this, say we leave first-line off to the side? That’s where CDK4/6 inhibitors are? We’ve all had women with ER-positive disease who struggle with the bone-related adverse events from aromatase inhibitors or some of the mucositis from the mTOR [mammalian target of rapamycin] inhibitors. When you look at the toxicity profiles, olaparib, in that setting, would be pretty well tolerated and very reasonable to use for someone with ER-positive disease in the second-line setting, if they are having a hard time with endocrine therapy.

Joyce O’Shaughnessy, MD: We all gauge it—how many lines of endocrine therapy we give depends on what’s going on with the patient. How well did they do with the previous endocrine therapy? Everybody is going to be different, in terms of how many lines of endocrine therapy they receive. But it sounds like we’re all on the same page. Before we would go on to our next option, like oral capecitabine, for example (which we might have done next), we’d go on to olaparib. So that’s really interesting. We’re moving it up, and it’s really going to be interesting to see how that goes for the patient. We really hope we get those wonderful, durable responses.